Indazole having analgesic activity

ABSTRACT

An intermediate of formula (II)

The present application is a divisional of U.S. Ser. No. 10/549,930,filed on Sep. 20, 2005, which is a National Stage (371) ofPCT/EP04/04390, filed on Apr. 23, 2004, which claims priority to ItalianApplication No. MI2003A 000972, filed on May 15, 2003.

The present invention relates to an indazole having analgesic activity,a method for the preparation thereof and a pharmaceutical compositioncontaining the same.

Chronic pain is very widespread. On average about 20% of the adultpopulation suffers from it, and it is generally associated with clinicalconditions characterized by chronic and/or degenerative lesions.

Typical examples of pathologies characterized by chronic pain arerheumatoid arthritis, osteoarthritis, fibromyalgia, neuropathies, etc.[Ashburn M A, Staats P S. Management of chronic pain. Lancet 1999; 353:1865-69].

Chronic pain is often debilitating and is the cause of loss of thecapacity for work and poor quality of life. Therefore it also hasadverse economic and social consequences.

The analgesic drugs currently used in the treatment of chronic painbelong basically to two classes: the non-steroidal anti-inflammatorydrugs (NSAIDs), which combine analgesic activity and anti-inflammatoryactivity, and the opioid analgesics. These classes constitute the basisfor the three-step “analgesic scale” suggested by the World HealthOrganization for drug treatment of pain [Textbook of Pain. 4th edition.PD Wall and R Melzack Eds. Churchill Livingstone, 1999].

Chronic pain is notoriously difficult to treat using the treatmentscurrently available. Consequently the development of new analgesics hasalways been one of the main aims of the pharmaceutical industry.Nevertheless, despite the extensive research efforts directed towardsidentifying a suitable analgesic compound, there is a significant numberof patients whose pain condition is still not being adequately treated[Scholz J, Woolf C J. Can we conquer pain? Nat Neusci. 2002; 5:1062-76].

Surprisingly, it has now been found that such properties are possessedby a new family of indazoles.

In its first aspect, the present invention thus relates to an indazoleof general formula:

where

-   X is C(O)NHCH₂, NHC(O) or NHC(O)CH₂;-   R_(a) is H, NH₂C(O), CH₃C(O)NH, CH₃SO₂, CH₃SO₂NH, linear or branched    C₁-C₃ alkyl, linear or branched C₁-C₃ alkoxy, or halogen;-   R_(b) is H, linear or branched C₁-C₆ alkyl; aryl-(C₁-C₃)alkyl    optionally substituted with 1 or 2 halogen atoms, with a C₁-C₃ alkyl    group or a C₁-C₃ alkoxy group;-   and in which-   a) when X is C(O)NHCH₂    -   R_(c) is hydroxy, amino, di-(C₁-C₃)alkyl-amino,        tri-(C₁-C₃)alkyl-ammoniomethyl, nitro, trifluoromethyl, nitrile,        CH₃C(O)NH, CH₃SO₂NH, CH₃SO₂, R′R″NSO₂, where R′ and R″ are H, or        a linear or branched C₁-C₆ alkyl,    -   R_(d) is H, hydroxy, amino, di-(C₁-C₃)alkyl-amino,        tri-(C₁-C₃)alkyl-ammoniomethyl, nitro, trifluoromethyl, nitrile,        CH₃C(O)NH, CH₃SO₂NH, CH₃SO₂, R′R″NSO₂, where R′ and R″ have the        meanings stated above,    -   with the proviso, however, that when R_(a) and R_(d) are both H,        and R_(b) is isopropyl, then R_(c) is not hydroxy;-   b) when X is NHC(O) or NHC(O)CH₂    -   R_(c) and R_(d), which may be equal or different, are H,        hydroxy, C₁-C₃ alkoxy, halogen, amino, di-(C₁-C₃)alkylamino,        tri-(C₁-C₃)alkyl-ammoniomethyl, nitro, trifluoromethyl, nitrile,        CH₃C(O)NH, CH₃SO₂NH, CH₃SO₂, R′R″NSO₂, where R′ and R″ have the        meanings stated above,        and their acid addition salts with pharmaceutically acceptable        organic and inorganic acids.

Typical examples of pharmaceutically acceptable acids are: oxalic,maleic, methanesulphonic, paratoluenesulphonic, succinic, citric,tartaric, lactic, hydrochloric, phosphoric, sulphuric.

-   Preferred meanings of R_(a) are H and C₁-C₃ alkyl.-   Preferred meanings of R_(b) are H and C₁-C₃ alkyl.-   Preferred meanings of R_(c) are H, NO₂, NH₂, OH and C₁-C₃ alkoxy.-   The preferred meaning of R_(d) is H.

The analgesic activity of the compounds of formula (I) was found bymeans of two experimental models in the rat: mechanical hyperalgesiainduced by CFA and mechanical hyperalgesia in diabetic neuropathyinduced by streptozocin.

As is known to a person skilled in the art, the aforementionedexperimental models can be regarded as predictive of activity in man.

CFA-induced hyperalgesia is a syndrome characterized by the activationof circuits with the task of controlling the inflammatory response andassociated with the appearance of conditions that interfere with theperception of pain. Injection of CFA is in fact capable of peripherallyinducing the release of specific substances (mediators of theinflammatory response and algogenic agents) responsible for local damageand centrally, at the level of the spinal cord, determining biochemicalchanges that support the amplification of the perception of pain. As iswell known, this model constitutes a valid tool for investigating drugsfor use in the treatment of inflammatory pain in man and, in particular,in the control of conditions such as hyperalgesia and allodynia.

Typical examples of human pathologies characterized by this type of painassociated with degenerative inflammatory processes are rheumatoidarthritis and osteoarthritis.

In its turn, the diabetic neuropathy induced by streptozocin in the ratrepresents an insulin-dependent syndrome characterized by a concomitantdecrease in the conduction velocity of the motor and sensory nerves andthe appearance of a number of anomalies in pain perception. As is wellknown, this experimental model constitutes a useful tool for theinvestigation of drugs for use in the treatment of neuropathic pain inman. In particular, the model represents a valid example of a whole hostof neuropathic pains characterized by phenomena such as hyperalgesia andallodynia following primary lesions or dysfunctions of the nervoussystem. Typical examples of human pathologies characterized bydysfunctions of this type and by the presence of neuropathic pain arediabetes, cancer, immunodeficiency diseases, trauma, ischaemias,multiple sclerosis, sciatic neuralgias, neuralgia of the trigeminalnerve and post-herpetic syndromes.

In a second aspect, the present invention relates to a method ofpreparation of a compound of formula (I) in which X═C(O)NHCH₂ and acidaddition salts thereof with pharmaceutically acceptable organic orinorganic acids, characterized in that it comprises the followingstages:

-   a) reaction of an amine of formula (II)

-   -   where    -   R_(c) and R_(d) have the same meanings as stated above or, when        R_(c) or    -   R_(d) is an amino or alcoholic group, R_(c) and R_(d) may be an        amino or    -   alcoholic group protected by a protective group of conventional        type,    -   with a derivative of an indazole-carboxylic acid of formula        (IIIa)

-   -   where    -   R_(a) and R_(b) have the meanings stated above, and    -   Y is a Cl or Br atom, or an OR or OC(O)R group, where R is a        linear    -   or branched alkyl having from 1 to 6 carbon atoms,    -   or with a derivative of an indazole-carboxylic acid of formula        (IIIb)

-   -   where    -   R_(a) has the meanings stated above,

-   b) cleavage of any possible protective group of the aforesaid amino    or alcoholic group, and

-   c) optional formation of an acid addition salt of the indazoleamide    of formula (I) with a pharmaceutically acceptable organic or    inorganic acid.

In a third aspect, the present invention relates to a method ofpreparation of a compound of formula (I) in which X═NH(CO) or NH(CO)CH₂and acid addition salts thereof with pharmaceutically acceptable organicor inorganic acids, characterized in that it comprises the followingstages:

-   a′) reaction of an amine of formula (IV)

-   where-   R_(a) and R_(b) have the meanings stated above,-   is condensed with a derivative of a carboxylic acid of formula (V)

-   where-   R_(c) and R_(d) have the same meanings as stated above or, when    R_(c) or R_(d) is an amino or alcoholic group, R_(c) and R_(d) may    be an amino or alcoholic group protected by a protective group of    conventional type, and-   Z is a group C(O)Y or CH₂C(O)Y in which Y is a Cl or Br atom, or an    OR or OC(O)R group, where R is a linear or branched alkyl having    from 1 to 6 carbon atoms,-   b′) cleavage of any possible protective group of the aforesaid amino    or alcoholic group, and-   c′) optional formation of an acid addition salt of the indazoleamide    of formula (I) with a pharmaceutically acceptable organic or    inorganic acid.

A person skilled in the art will easily understand that some compoundsof formula (I) can also be prepared from another compound of formula (I)by conventional techniques. For example, when R_(c) and/or R_(d) are anNO₂ group the latter can be reduced to give the corresponding compoundof formula (I) in which R_(c) and/or R_(d) are NH₂.

The amine of formula (II) may be obtained according to conventionalmethods. For example, by alkylation of isonipecotamide with a suitablehalide and then reduction of the amide to primary amine (WO 9807728) orby protection of aminomethylpiperidine with benzaldehyde (SyntheticCommunications 22(16), 2357-2360, 1992), alkylation with a suitablehalide and deprotection.

The intermediate of formula (II) in which R_(c) and R_(d) have themeanings stated above is novel. This intermediate therefore is anotheraspect of the present invention.

The compounds of formula (IIIa) and (IIIb) may also be obtainedaccording to conventional methods. For example, the compounds of formula(IIIa) in which Y is chlorine may be obtained from the correspondingacid with thionyl chloride (J. Med. Chem., 1976, Vol. 19 (6), pages778-783), whereas the compounds of formula (IIIa) in which Y is OR orOC(O)R may be obtained by means of known reactions of esterification orof formation of mixed anhydrides (R. C. Larok, Comprehensive OrganicTransformations, VCH, pages 965-966). In their turn, the compounds offormula (IIIb) may be obtained according to J.O.C. 1958, Vol. 23 page621.

In their turn the compounds of formula (IV) may be obtained according tothe conventional methods described in the literature, for example in J.of Heterocyclic Chemistry 1979 (16) 783-784, or in J.A.C.S., 1943 (65)1804-1806.

The compounds of formula (V) may also be obtained according toconventional methods. For example, the compounds of formula (V) in whichY is chlorine may be obtained by saponification of the correspondingesters followed by treatment with thionyl chloride.

Preferably, stages (a) and (a′) are carried out by reacting

-   a compound of formula (II) with a compound of formula (IIIa) in    which Y is chlorine, or-   a compound of formula (II) with a compound of formula (IIIb), or-   a compound of formula (IV) with a compound of formula (V) in which Y    is chlorine,    in the presence of a suitable diluent and at a temperature of from 0    to 140° C., for a time of from 0.5 to 20 hours.

Preferably, the reaction temperature is of from 15 to 40° C.Advantageously, the reaction time is of from 1 to 18 hours.

Preferably the diluent is aprotic, polar or nonpolar. Even morepreferably it is aprotic nonpolar. Examples of suitable aprotic nonpolardiluents are the aromatic hydrocarbons, e.g. toluene. Examples ofsuitable aprotic polar diluents are dimethylformamide anddimethylsulphoxide.

In the embodiments in which a compound of formula (II) is reacted with acompound of formula (IIIa) in which Y is chlorine, or in which acompound of formula (IV) is reacted with a compound of formula (V) inwhich Y is chlorine, the aforesaid stages (a) and, respectively, (a′)are preferably carried out in the presence of an organic or inorganicacceptor of acids.

Examples of suitable organic acceptors of acids are pyridine,triethylamine and the like. Examples of suitable inorganic acceptors ofacids are alkali carbonates and bicarbonates.

In stages (b) and (b′), cleavage of the protective group of the amino oralcoholic group is preferably carried out by techniques known in thechemistry of protective groups.

In their turn, stages (c) and (c′) are preferably preceded by a stage ofisolation of the indazoleamide of formula (I).

In a further aspect, the present invention relates to a pharmaceuticalcomposition containing an effective amount of a compound of formula (I),or of an addition salt thereof with a pharmaceutically acceptable acid,and at least one pharmaceutically acceptable inert ingredient.

A typical example of a pathologic state that might benefit fromtreatment with a pharmaceutical composition according to the presentinvention is chronic pain. Typically this chronic pain is due to chroniclesions or to degenerative processes such as rheumatoid arthritis,osteoarthritis, fibromyalgia, oncologic pain, neuropathic pain and thelike.

Preferably, the pharmaceutical compositions of the present invention areprepared in a suitable dosage form.

Examples of suitable dosage forms are tablets, capsules, coated tablets,granules, solutions and syrups for oral administration; creams,ointments and medicated patches for topic administration; suppositoriesfor rectal administration and sterile solutions for injectable, aerosolor ophthalmic administration.

Advantageously, these dosage forms will be formulated in such a way asto provide controlled release over time of the compound of formula (I)or of a salt thereof with a pharmaceutically acceptable acid. Indeed,depending on the type of treatment, the required time of release may bevery short, normal or protracted.

The dosage forms may also contain other conventional ingredients suchas: preservatives, stabilizers, surfactants, buffers, salts for theregulation of the osmotic pressure, emulsifiers, sweetener agents,coloring agents, flavouring agents and the like.

Moreover, when required by particular therapies, the pharmaceuticalcomposition of the present invention may contain other pharmacologicallyactive ingredients whose concomitant is therapeutically useful.

The amount of the compound of formula (I) or of the pharmaceuticallyacceptable acid salt thereof in the pharmaceutical composition of thepresent invention may vary in a wide range depending on known factors,such as for example the type of disease to be treated, the severity ofthe disease, the patient's body weight, the dosage form, the chosenroute of administration, the number of daily administrations and theefficacy of the chosen compound of formula (I). However, the optimumamount may be easily and routinely determined by a person skilled in theart.

Typically, the amount of the compound of formula (I) or of a saltthereof with a pharmaceutically acceptable acid in the pharmaceuticalcomposition of the present invention will be such that it ensures anadministration level of from 0.001 to 100 mg/kg/day. Even morepreferably, of from 0.1 to 10 mg/kg/day.

The dosage forms of the pharmaceutical composition of the presentinvention can be prepared according to techniques that are well known tothe pharmaceutical chemist and comprise mixing, granulation,compression, dissolution, sterilization and the like.

The following examples will illustrate the invention, without limitingit in any way.

In the following examples, the substituents on the aromatic ring (R_(c)and R_(d)) are indicated with numbering in bold.

EXAMPLE 1(N((1-(2-(4-nitrophenyl)ethyl)-4-piperidinyl)methyl)-1H-indazole-3-carboxamidehydrochloride (AF3R298) (I, R_(a)═R_(b)═R_(d)═H; R_(c)=4-NO₂;X═C(O)NHCH₂) a) N-hexahydro-4-pyridinylmethyl-N-phenylmethylidene-amine

Benzaldehyde (4.6 g; 0.044 mol) was added dropwise to a solution of4-aminomethylpiperidine (5.0 g; 0.044 mol) in toluene (20 ml). Thesolution thus obtained was stirred for 3 h at room temperature. Then thesolvent was removed by evaporation at reduced pressure and the residuewas taken up twice with toluene to give the desired product that wasused as such without further purification.

b) 1-(2-(4-nitrophenyl)ethyl)-4-piperidinylmethane-amine

The product of Example 1a) (8.8 g; 0.044 mol) was dissolved in absoluteethanol (50 ml) and added to a suspension containing2-(4-nitrophenyl)ethylbromide (10.0 g; 0.044 mol) and anhydrouspotassium carbonate (12.1 g; 0.088 mol) in absolute ethanol (100 ml).The suspension thus obtained was boiled under reflux for 16 hours. Thereaction mixture was then left to cool to room temperature and filtered.The filtrate was evaporated at reduced pressure. The residue thusobtained was then suspended in 3N HCl (50 ml) and stirred for 3 h atroom temperature. The solution was then transferred to a separatoryfunnel and the acid aqueous phase was washed with ethyl acetate (4×50ml), the aqueous phase was then made alkaline by addition of 6N NaOH andextracted with dichloromethane. The organic phase was dried over NaSO₄and the solvent was removed by evaporation at reduced pressure to givethe desired product (9 g).

¹H-NMR (δ, CDCl3+D2O): 1.43-1.50 (m, 3H); 1.76 (d J=12 Hz, 2H); 2.03 (t,J=12 Hz, 2H); 2.67-2.52 (m, 4H); 2.82-3.06 (m, 4H); 7.39 (d, J=9 Hz,2H); 8.12 (d, J=9 Hz, 2H); 7.95 (quintet, J=1 Hz, 1H).

c)—N((1-(2-(4-nitrophenyl)ethyl)-4-piperidinyl)methyl)-1H-indazole-3-carboxamidehydrochloride

A solution of the product of Example 1b) (8.4 g; 0.032 mol) in toluene(85 ml) was added, using a dropping funnel, to a suspension containing7H,14H-indazole(2′,3′:4,5)pyrazine(1,2-b)indazole-7,14,dione (4.6 g;0.016 mol) prepared as described in J.O.C., 1958, Vol. 23, page 621, intoluene (60 ml). The reaction mixture was stirred at room temperaturefor 38 hours and then filtered. The solid was separated and added to astirred saturate solution of NaHCO₃ (200 ml) for 2 h. The reactionmixture was filtered and the thus obtained solid product was convertedinto the corresponding hydrochloride by dissolution in absolute ethanol,addition of hydrogen chloride in ethanol and recrystallization fromethanol, to give the desired product (4.2 g).

m.p.: 251-252.5° C.

Elemental analysis for C₂₂H₂₅N₅O₃.HCl

C H N Found % 59.60 5.96 15.77 Calculated % 59.52 5.90 15.78

¹H-NMR (δ, DMSO): 1.52-2.11 (m, 5H); 2.85-302 (m, 2H); 3.17-3.64 (m,8H); 7.19-7.28 (m, 1H); 7.36-7.46 (m, 1H); 7.53-7.56 (m, 3H); 8.13-8.26(m, 3H); 8.55 (t, J=6 Hz, 1H); 10.82 (s broad, 1H); 13.70 (s, 1H).

EXAMPLE 2N((1-(2-(4-aminophenyl)ethyl)-4-piperidinyl)methyl)-1H-indazole-3-carboxamidedihydrochloride (AF3R02) (I, R_(a)═R_(b)═R_(d)═H, R_(c)=4-NH₂,X═C(O)NHCH₂)

A solution of the product of Example 1c) in the form of base (3 g; 0.007mol) in 95° ethanol (200 ml) was hydrogenated on 10% Pd—C (0.3 g) at 40psi for 3 hours. The mixture was then filtered and the filtrate wasconcentrated at reduced pressure. The thus obtained product wascrystallized from ethyl acetate and transformed into the correspondinghydrochloride by dissolution in a mixture of ethyl acetate:ethanol=9:1and addition of hydrogen chloride in ethanol to give the desired product(1.2 g).

m.p.: 271-273° C. (decomp.)

Elemental analysis for C₂₂H₂₇N₅O.2HCl½H₂O

C H N Found % 57.31 6.68 15.05 Calculated % 57.52 6.58 15.24

¹H-NMR (δ, DMSO+D₂O): 1.45-1.66 (m, 2H); 1.80-2.00 (m, 3H); 2.86-3.14(m, 4H); 3.19-3.35 (m, 4H); 3.46-3.80 (m, 2H+HDO); 7.22-7.35 (m, 3H);7.35-7.49 (m, 3H); 7.64 (d, J=9 Hz; 1H); 8.17 (d, J=9 Hz, 1H).

EXAMPLE 3N((1-(2-(4-nitrophenyl)ethyl)-4-piperidinyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamideoxalate (AF3R306) (I, R_(a)═R_(d)═H, R_(b)=i-C₃H₇, R_(c)=4-NO₂,X═C(O)NHCH₂)

1-(1-methylethyl)-1H-indazole-3-carboxylic acid chloride (2.45 g; 0.011mol), prepared as described in EP-B1-0 975 623, was added portionwise toa solution of product 1b) (3.0 g; 0.011 mol) and of triethylamine (4.6ml; 0.033 mol) in toluene (50 ml). The mixture was stirred at roomtemperature for 18 h. The solvent was removed by evaporation at reducedpressure. The residue was taken up with 1N NaOH and dichloromethane. Themixture was transferred to a separately funnel. The organic phase wasseparated and dried over Na₂SO₄. The solvent was removed by evaporationat reduced pressure and the residue thus obtained was purified by flashchromatography, eluting with ethyl acetate to give the desired product(5.5 g) which was then transformed into the corresponding oxalate bydissolution in ethyl acetate, addition of a stoichiometric amount ofoxalic acid and recrystallization from ethyl acetate:ethanol=9:1, twice,to give the desired salt (3.5 g).

m.p.: 98° C. (decomp.)

Elemental analysis for C₂₅H₃₁N₅O₃.C2H2O4½H₂O

C H N Found % 59.27 6.15 12.72 Calculated % 59.11 6.25 12.77

¹H-NMR (δ, DMSO+D₂O): 1.55 (d, J=7 Hz, 6H); 1.44-1.66 (m, 2H); 1.83-2.02(m, 3H); 2.98 (t, J=12 Hz, 2H); 3.10-3.40 (m, 6H); 3.55 (d, J=12 Hz,2H); 5.07 (heptet, J=7 Hz, 1H); 7.28 (t, J=8 Hz, 1H); 7.46 (t, J=7 Hz,1H); 7.59 (d, J=9 Hz; 2H); 7.79 (d, J=8 Hz; 1H); 8.11-8.26 (m, 3H); 8.42(t, J=6 Hz, 1H).

EXAMPLE 4N((1-(2-(4-aminophenyl)ethyl)-4-piperidinyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamidedihydrochloride (AF3R294) (I, R_(a)═R_(d)═H, R_(b)=i-C₃H₇, R_(c)=4-NH₂,X═C(O)NHCH₂)

A solution of the product of Example 3, in the form of base, (2.7 g;0.006 mol) in 95° ethanol (30 ml) was hydrogenated on 10% Pd—C (0.27 g)at 40 psi for 5 hours. The mixture was then filtered and the filtratewas concentrated at reduced pressure. The product thus obtained wastransformed into the corresponding hydrochloride by dissolution in ethylacetate, addition of hydrogen chloride in ethanol and recrystallizationfrom a mixture of ethyl acetate:ethanol=8:2, to give the desired product(1.4 g).

m.p.: 278° C. (decomp.)

Elemental analysis for C₂₅H₃₃N₅O.2HCl H₂O

C H N Found % 59.05 7.42 13.63 Calculated % 58.82 7.31 13.72

¹H-NMR (δ, DMSO): 1.55 (d, J=7 Hz, 6H); 1.45-2.13 (m, 5H); 2.80-3.64 (m,10H); 5.08 (heptet, J=7 Hz, 1H); 7.20-7.49 (m, 6H); 7.79 (d, J=9 Hz;1H); 8.18 (d, J=9 Hz, 1H) 8.39 (t, J=6 Hz, 1H); 9.15-11.18 (m, 4H)

EXAMPLE 5N-(1-methyl-1H-indazol-3-yl)-1-(2-phenylethyl)piperidine-4-carboxamidehydrochloride (AF3R334) (I, R_(a)═R_(c)═R_(d)═H, R_(b)═CH₃, X═NHC(O)) a)1-(2-phenylethyl)-4-piperidine-carboxylic acid hydrochloride

A suspension of 1-(2-phenylethyl)-4-carbetoxypiperidine (12.2 g, 0.047mol) obtained as described in J. Med. Chem. 1996 (39), 749-756, in 1NNaOH (100 ml) was heated under reflux for 4 h. After cooling to roomtemperature, the solution was made acid with 6N HCl to pH 2,concentrated by evaporation at reduced pressure, and the solid thusobtained was filtered and dried in a stove under vacuum to give thedesired product (12.1 g),

¹H-NMR (δ, DMSO+D₂O): 1.79-2.19 (m, 4H); 2.43-3.74 (m, 9H); 7.18-7.41(m, 5H);

b) 1-(2-phenylethyl)-4-piperidinecarbonyl chloride hydrochloride

A suspension of the product of Example 5a) (2.0 g; 0.007 mol) and ofthionyl chloride (0.81 ml; 0.011 mol) in toluene (20 ml) was heatedunder reflux for 3 h. The solvent was then removed by evaporation atreduced pressure and the residue was taken up with toluene (2×20 ml) togive the desired product (2.2 g) that was used as such without furtherpurification.

c)N-(1-methyl-1H-indazol-3-yl)-1-(2-phenylethyl)piperidine-4-carboxamidehydrochloride

The product of Example 5b) (1.68 g; 0.006 mol) was added to a solutionof 1-methyl-1H-3-indazoleamine (0.86 g; 0.006 mol), prepared asdescribed in the Journal of Heterocyclic Chemistry 1979 (16), 783-784,and of triethylamine (2.4 ml; 0.018 mol) in toluene (20 ml). Thereaction mixture was stirred at room temperature for 18 h and then thesolvent was removed by evaporation at reduced pressure. The residue thusobtained was taken up with 1N NaOH and dichloromethane and transferredto a separatory funnel. The organic phase was separated, dried overNa₂SO₄ and the solvent was removed by evaporation at reduced pressure.The product thus obtained was transformed into the correspondinghydrochloride by dissolution in ethanol, addition of hydrogen chloridein ethanol and recrystallization from ethanol, to give the desired salt(1.6 g).

m.p.: 235-237° C.

Elemental analysis for C22H26N₄O.HCl¼H₂O

C H N Found % 65.71 6.80 13.73 Calculated % 65.50 6.87 13.89

¹H-NMR (δ, DMSO D2O): 1.91-2.27 (m, 4H) 2.70-3.42 (m, 7H); 3.63-3.75 (m,2H); 3.96 (s, 3H); 7.10 (t, J=8 Hz, 1H); 7.22-7.46 (m; 6H); 7.56 (d, J=8Hz, 1H) 7.74 (d, J=8 Hz, 1H); 10.51 (s, 1H)

EXAMPLE 6N-(1-methyl-1H-indazol-3-yl)-1-(2-(4-methoxyphenyl)ethyl)piperidine-4-carboxamidehydrochloride (AF3R328) (I, R_(a)═R_(d)═H, R_(b)═CH₃, R_(c)=4-OCH₃,X═NHC(O)) a) 1-(2-(4-methoxyphenyl)ethyl)-4-piperidine-carboxylic acidhydrochloride

The title product was obtained (15.8 g) by working in a similar way tothat described in Example 5a) but starting from1-(2-(4-methoxyphenyl)ethyl)-4-carbetoxypiperidine (16.5 g; 0.057 mol),prepared as described in U.S. Pat. No. 6,017,931, instead of from1-(2-phenylethyl)-4-carbetoxypiperidine.

¹H-NMR (δ, DMSO): 1.80-2.17 (m, 4H); 2.41-3.74 (m, 7H); 3.73-(s, 3H);6.89 (d, J=9 Hz, 2H); 7.19 (d, J=9 Hz, 2H) 11.00 (s broad, 1H); 12.53 (sbroad, 1H)

b) 1-(2-(4-methoxyphenyl)ethyl)-4-piperidinecarbonyl chloridehydrochloride

The title product was obtained (14.2 g) starting from the product ofExample 6a) (13.8 g; 0.048) and by working in a similar way to thatdescribed in example 5b). The product thus obtained was used as suchwithout further purification.

c)N-(1-methyl-1H-indazol-3-yl)-1-(4-methoxyphenyl)ethyl)piperidine-4-carboxamidehydrochloride

The title product was obtained (9.2 g) starting from the product ofExample 6b) (14.2 g; 0.045 mol) and from 1-methyl-1H-3-indazoleamine(6.6 g; 0.045 mol) and by working in a way similar to that described inExample 5c). A mixture of ethyl acetate:ethanol 9:1 was used as thecrystallization solvent.

m.p.: 137-139° C. (decomp.)

Elemental analysis for C₂₃H₂₈N₄O₂.HClH₂O

C H N Found % 61.80 7.14 12.45 Calculated % 61.80 6.99 12.53

¹H-NMR (δ, DMSO): 1.95-2.25 (m, 4H) 2.69-3.48 (m, 7H); 3.57-3.70 (m,2H); 3.74 (s, 3H); 3.96 (s, 3H); 6.92 (d, J=9 Hz, 2H); 7.08 (t, J=9 Hz,1H); 7.20 (d, J=9 Hz, 2H); T38 (t, J=8 Hz, 1H); 7.56 (d, J=9 Hz, 1H);7.76 (d, J=8 Hz, 1H); 10.36-11.07 (m, 2H)

EXAMPLE 7N-(1-methyl-1H-indazol-3-yl)-1-2-4-hydroxyphenyl)ethyl)piperidine-4-carboxamidehydrochloride (AF3R330) (I, R_(a)═R_(d)═H, R_(b)═CH₃, R_(c)=4-OH,X═NHC(O))

A solution of the product of Example 6c) (6.7 g; 0.017 mol) indichloromethane (300 ml) was added dropwise to a solution of BBr₃ (8.5g; 0.034 mol) in dichloromethane (50 ml). The reaction mixture wasstirred at room temperature for 6 h. Then water was added carefully andthe mixture was made alkaline with 1N NaOH to pH=9 and transferred to aseparatory funnel. The organic phase was separated, dried over Na₂SO₄,and the solvent was removed by evaporation at reduced pressure. Theresidue thus obtained (4.4 g) was purified by flash chromatography usinga mixture CHCl₃:MeOH=9:1 as eluent. 3 g of product were thus obtained,and were transformed into the corresponding hydrochloride by dissolutionin ethanol, addition of hydrogen chloride in ethanol, evaporation of thesolvent and crystallization from a mixture of ethyl acetate:ethanol 9:1,to give the desired product (2.8 g).

m.p.: 249-252° C.

Elemental analysis for C₂₂H₂₆N₄O₂.HCl⅔H₂O

C H N Found % 62.14 6.64 13.45 Calculated % 61.91 6.69 13.13

¹H-NMR (δ, DMSO): 1.96-2.25 (m, 4H) 2.67-3.47 (m, 7H); 3.63 (d, J=12 Hz,2H); 3.95 (s, 3H); 6.69-6.80 (m, 2H); 7.00-7.13 (m, 3H); 7.38 (t, J=9Hz, 1H); 7.56 (d, J=9 Hz, 1H); 7.76 (d, J=9 Hz, 1H); 9.37 (s broad, 1H);10.35-10.90 (m, 2H)

EXAMPLE 8N((1-(2-(4-hydroxyphenyl)ethyl)-4-piperidinyl)methyl)-5-methyl-1-(1-methylethyl)-1H-indazole-3-carboxamidehydrochloride (AF3R296) (I, R_(a)═CH₃, R_(b=i-C) ₃H₇, R_(c)=4-OH,R_(d)═H, X═C(O)NHCH₂) a)1-(2-(4-hydroxyphenyl)ethyl)-4-piperidinylmethane-amine

The title product was obtained (9.3 g) by working in a similar way tothat described in Example 1b) but starting from the product of Example1a) (7.5 g, 0.037 mol) and 2-(4-hydroxyphenyl)ethyl bromide (7.5 g;0.037 mol), prepared as described in Acta Chemica Scandinava (1947-1973)1967, 21 (1), 52-62, instead of from 2-(4-nitrophenyl)ethyl bromide.

¹H-NMR (δ, CDCl3+D2O): 1.15-1.41 (m, 3H); 1.74 (d, J=9 Hz, 2H);1.90-2.07 (m, 2H); 2.45-2.61 (m, 4H); 2.65-2.75 (m, 2H); 3.01 (d, J=12Hz, 2H); 6.75 (d, J=9 Hz, 2H); 7.00 (d, J=9 Hz, 2H).

b) isopropyl ester of 1(1-methylethyl)-5-methyl-1H-indazole-3-carboxylicacid

A 60% suspension of sodium iodide in mineral oil (17.1 g; 0.43 mol) wasadded to a suspension of 5-methyl-1H-indazole-3-carboxylic acid (30 g;0.17 mol) prepared as described in J. Heterocyclic Chem. 1964, Vol. 1(5) 239-241, in dimethylformamide (450 ml), and the reaction mixture washeated to 70° C. After 30 minutes, isopropyl bromide (48 ml, 0.51 mol)was added.

The reaction mixture was stirred for 6 hours at 70° C. After cooling,water was added. The reaction mixture was transferred to a separatoryfunnel and extracted with diethyl ether. The organic phase was washedwith water saturate with sodium bicarbonate and, finally, the solventwas removed by evaporation at reduced pressure.

In this way 20 g of an oil were obtained, which were purified by flashchromatography, eluting with a mixture hexane:ethyl acetate=7:3, to give12 g of the desired product.

¹H-NMR (δ, CDCl3): 1.47 (d, J=6 Hz, 6H); 1.64 (d, J=7 Hz, 6H); 2.50 (d,J=1 Hz, 3H); 4.92 (heptet, J=7 Hz, 1H); 5.39 (heptet, J=6 Hz, 1H); 7.23(dd, J=9; 1 Hz, 1H); 7.40 (d, J=9 Hz, 1H); 7.95 (quintet, J=1 Hz, 1H).

c) 1-(1-methylethyl)-5-methyl-1H-indazole-3-carboxylic acid

A suspension of the product prepared according to Example 8b) (8 g; 0.03mol) in 1M NaOH (42 ml) was heated under reflux for 3 hours. It was thenpoured into water, acidified with 2M HCl and extracted withdichloromethane. After evaporation of the solvent at reduced pressure, 7g of the desired product were obtained.

¹H-NMR (δ, CDCl3): 1.61 (d J=7 Hz, 6H); 2.44 (s, 3H); 4.88 (heptet, J=7Hz, 1H); 7.19 (d, J=9 Hz, 1H); 7.34 (d, J=9 Hz, 1H); 7.97 (s, 1H); 9.32(s broad, 1H).

d) chloride of 1-(1-methylethyl)-5-methyl-1H-indazole-3-carboxylic acid

Thionyl chloride (6.78 g; 0.057 mol) was added to a suspension of theproduct prepared according to Example 8c) (4.01 g; 0.019 mol) in toluene(70 ml), and the reaction mixture was heated under reflux for 2 hours.The solvent was removed by evaporation at reduced pressure and taken uptwice with toluene (50 ml×2) to give the desired product (4.3 g) whichwas used as such without further purification.

e)N((1-(2-(4-hydroxyphenyl)ethyl)-4-piperidinyl)methyl)-5-methyl-1-(1-methylethyl)-1H-indazole-3-carboxamidehydrochloride

Working in a similar way to that described in Example 3 but using theproduct of Example 8a) (4.0 g, 0.017 mol) and the chloride of1-(1-methylethyl)-5-methyl-1H-indazole-3-carboxylic acid (4.0 g, 0.017mol), prepared as described in the preceding Example 8d), 4.5 g of thedesired product were obtained, and this were transformed into thecorresponding hydrochloride by dissolution in absolute ethanol, additionof hydrogen chloride in ethanol and recrystallization from ethanol togive the desired salt (3.2 g).

m.p.: 257.5-259.5° C.

Elemental analysis for C₂₆H₃₄N₄O₂HCl

C H N Found % 66.20 7.75 11.87 Calculated % 66.30 7.49 11.89

¹H-NMR (δ, DMSO): 1.53 (d, J=7 Hz, 6H); 1.44-1.76 (m, 3H); 1.87 (d, J=12Hz, 2H); 2.42 (s, 3H); 2.79-3.45 (m, 8H); 3.54 (d, J=12 Hz, 2H); 5.03(heptet, J=7 Hz, 1H); 6.73 (d, J=9 Hz, 2H); 7.05 (d, J=9 Hz, 2H); 7.26(d,d J=9.2 Hz, 1H); 7.67 (d, J=9 Hz; 1H); 7.96 (s, 1H); 8.30 (t, J=6 Hz,1H); 9.35 (s, 1H); 10.35 (s broad, 1H),

TESTS

1. Mechanical Hyperalgesia Induced by CFA in the Rat

Male CD rats weighing 150-200 g on arrival were used. Using ananalgesiometer, rats were selected having a response threshold to amechanical nociceptive stimulus of from 150 to 180 g. By applying agradual increase in pressure on the dorsal zone of the rat's left hindfoot, the instrument makes it possible to record the nocifensiveresponse, expressed in grams, corresponding to the moment when theanimal retracts its foot [Randall L O and Semite J J. A method for themeasurement of analgesic activity on inflamed tissue. Arch. Int.Pharmacodyn. Ther. 1957; 111: 409-419].

Hyperalgesia was induced by unilateral injection of 150 μl of CompleteFreund's Adjuvant (CFA) in the plantar surface of the animal's left hindfoot [Andrew D, Greenspan J D. Mechanical and heat sensitization ofcutaneous nociceptors after peripheral inflammation in the rat. JNeurophysiol 1999; 82(5): 2649-2656; Hargreaves K, Dubner R, Brown R,Flores C, Joris J. A new and sensitive method for measuring thermalnociception in cutaneous hyperalgesia. Pain 1988; 32: 77-88].

The compounds under examination were tested (dose 10⁻⁵ mol/kg) bycarrying out the test 23 hours after injection of CFA.

At 1 h following the treatment, the pain threshold measured in controlanimals was compared with that measured in animals treated with theproduct under examination. The control animals were treated with thesame vehicle (water) used for administering the products underexamination. The results are shown in Table 1.

TABLE 1 Effect on CFA Pain threshold (g) 1 h after Treatment Number ofrats treatment Vehicle 12 121 ± 4.1  AF3R294 12 194 ± 22.4 AF3R296 12151 ± 10.7 AF3R298 12 174 ± 9.8  AF3R302 12 160 ± 10.2 AF3R306 12 186 ±11.0 AF3R328 12 150 ± 8.7  AF3R330 12 161 ± 10.5 AF3R334 12 170 ± 11.0The pain threshold of normal animals of equal weight/age=155±2.1 g2. Mechanical Hyperalgesia in Rats with Diabetes Induced byStreptozotocin

Male CD rats weighing 240-300 g on arrival were used.

Diabetic syndrome was induced by a single intraperitoneal (i.p.)injection of 80 mg/kg of streptozotocin dissolved in sterilephysiological solution [Courteix C, Eschalier A, Lavarenne J.Streptozotocin-induced diabetic rats: behavioural evidence for a modelof chronic pain. Pain, 1993; 53: 81-88; Bannon A W, Decker M W, Kim Dj,Campbell J E, Arneric S P. ABT-594, a novel cholinergic channelmodulator, is efficacious in nerve ligation and diabetic neuropathymodels of neuropathic pain. Brain Res. 1998; 801: 158-63].

After at least three weeks following the injection of streptozotocin,rats were selected having a level of glycaemia ≧300 mg/dl and having aresponse threshold to a mechanical nociceptive stimulus ≦120 g. Theglycaemia levels were measured by means of a reflectometer usingreactive strips impregnated with glucose oxidase. The pain threshold wasmeasured using an analgesiometer. By applying a gradual increase inpressure on the dorsal zone of the rat's left hind foot, the instrumentmakes it possible to record the nocifensive response, expressed ingrams, corresponding to the moment when the animal retracts its foot.

At 2 h following the treatment, the pain threshold measured in controlanimals was compared with that measured in animals treated with theproduct under examination (dose 10⁻⁵ mol/kg).

The control animals were treated with the same vehicle (water) used foradministering the products under examination. The results are shown inTable 2.

TABLE 2 Effect on diabetic neuropathy Pain threshold (g) 2 h afterTreatment Number of rats treatment Vehicle 8 112 ± 4.0  AF3R294 8 198 ±18.6 AF3R296 8 154 ± 8.7  AF3R298 8 170 ± 10.2 AF3R302 8 164 ± 10.2AF3R306 8 184 ± 13.8 AF3R328 8 158 ± 6.2  AF3R330 8 171 ± 9.6  AF3R334 8184 ± 10.5The pain threshold of normal animals of equal weight/age=240±8.7 g

What we claim is:
 1. An intermediate of formula (II)

where R_(c) is hydroxy, amino, di-(C₁-C₃)alkyl-amino,tri-(C₁-C₃)alkyl-ammoniomethyl, nitro, trifluoromethyl, nitrile,CH₃C(O)NH, CH₃SO₂NH, CH₃SO₂, R′R″NSO₂, where R′ and R″ are H, or linearor branched C₁-C₆ alkyl, R_(d) is H, hydroxy, amino,di-(C₁-C₃)alkyl-amino, tri-(C₁-C₃)alkylammoniomethyl, nitro,trifluoromethyl, nitrile, CH₃C(O)NH, CH₃SO₂NH, CH₃SO₂, R′R″NSO₂, whereR′ and R″ are H, or linear or branched C₁-C₆ alkyl.
 2. The intermediateof claim 1, wherein R_(c) is a hydroxyl group.
 3. The intermediate ofclaim 1, wherein R_(c) is an amino group.
 4. The intermediate of claim1, wherein R_(c) is a di-(C₁-C₃)alkyl-amino group.
 5. The intermediateof claim 1, wherein R_(c) is a tri-(C₁-C₃)alkyl-ammoniomethyl group. 6.The intermediate of claim 1, wherein R_(c) is a nitro group.
 7. Theintermediate of claim 1, wherein R_(c) is a trifluoromethyl group. 8.The intermediate of claim 1, wherein R_(c) is a nitrile group.
 9. Theintermediate of claim 1, wherein R_(c) is a CH₃C(O)NH group.
 10. Theintermediate of claim 1, wherein R_(c) is a CH₃SO₂NH group.
 11. Theintermediate of claim 1, wherein R_(c) is a CH₃SO₂ group.
 12. Theintermediate of claim 1, wherein R_(c) is a R′R″NSO₂, where R′ and R″are H, group.
 13. The intermediate of claim 1, wherein R_(c) is a linearC₁-C₆ alkyl group.
 14. The intermediate of claim 1, wherein R_(c) is abranched C₁-C₆ alkyl group.
 15. The intermediate of claim 1, whereinR_(d) is H.
 16. The intermediate of claim 1, wherein R_(d) is a hydroxylgroup.
 17. The intermediate of claim 1, wherein R_(d) is an amino group.18. The intermediate of claim 1, wherein R_(d) is adi-(C₁-C₃)alkyl-amino group.
 19. The intermediate of claim 1, whereinR_(d) is a tri-(C₁-C₃)alkyl-ammoniomethyl group.
 20. The intermediate ofclaim 1, wherein R_(d) is a nitro group.
 21. The intermediate of claim1, wherein R_(d) is a trifluoromethyl group.
 22. The intermediate ofclaim 1, wherein R_(d) is a nitrile group.
 23. The intermediate of claim1, wherein R_(d) is a CH₃C(O)NH group.
 24. The intermediate of claim 1,wherein R_(d) is a CH₃SO₂NH group.
 25. The intermediate of claim 1,wherein R_(d) is a CH₃SO₂ group.
 26. The intermediate of claim 1,wherein R_(d) is a R′R″NSO₂, where R′ and R″ are H, group.
 27. Theintermediate of claim 1, wherein R_(d) is a linear C₁-C₆ alkyl group.28. The intermediate of claim 1, wherein R_(d) is a branched C₁-C₆ alkylgroup.